JP2001527020A - Manufacturing method of apatite ceramics especially for biological use - Google Patents

Abstract

(57) [Summary] The present invention particularly relates to a method for producing apatite ceramics for biological use. The method comprises the steps of preparing a homogeneous mixture of powders capable of forming stoichiometric or non-stoichiometric hydroxyapatite of the formula Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ , optionally containing further additives. Compressing the mixture at room temperature under a pressure of 100-500 MPa, and subjecting the mixture to thermohydration at a low temperature (100-500 ° C.) in the presence of water in a closed chamber.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates to a method for producing apatite ceramics, which is particularly useful for producing apatite for biological use.

Apatite is a useful material in a variety of fields, for example, fertilizers in agriculture, biomaterials in orthopedic surgery, and chromatographic supports in analytical chemistry.

Apatite has the general formula: Me ₁₀ (XO ₄ ) ₆ Y ₂ (I) wherein Me represents one or more cations, XO ₄ represents PO ₄ and / or another anionic group, Y represents one or more anions such as OH, Cl and F]. Among these apatites, calcium phosphates (ph
Ospocalcic) hydroxyapatite: Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ (II) is the most well-known compound.

[0004] The apatite of formula (I) can be variously substituted both at the cation site (Me) and at the anion site (XO ₄ and / or Y ₂ ).

[0005] Depending on the various intended uses, these replaceable properties may be exploited to improve the physical and / or chemical properties of apatite.

[0006] Further, apatites, especially apatites of formula (II), may be non-stoichiometric.
That is, the atomic ratio of calcium / phosphorus is 1.6 of the stoichiometric apatite of the formula (II).
It may have a value different from 77.

[0007] For non-stoichiometric apatite this ratio is generally less than 1.677. Cause of such a non-stoichiometric amounts in particular, due to the presence of voids in the cationic / calcium sites, and / or a order to present HPO ₄ ^2-ions are replaced with phosphate ions. Apatite has the general formula: Ca _10-x V _x (PO ₄ ) _6-y (HPO ₄ ) _y (OH) _{2 + y-2x} (III) wherein V represents a void, and x and y are x <1, y <1 and y ≦ x]. When x = y = 0, apatite is stoichiometric.

[0008] Among the apatites, the existence of non-stoichiometric bioapatite that forms the inorganic portion of hard tissue and the teeth and bones is known.

Apatite is used in the fields of biology, orthopedics or dentistry because apatite is completely biocompatible. The cause of this biocompatibility is that the structure and composition of hydroxyapatite is very close to the structure and composition of the mineral part of the calcified tissue. Most calcium orthophosphates, including tricalcium phosphate, dicalcium phosphate and octocalcium phosphate, also have excellent biocompatibility. It has been recognized that hydroxyapatite, and more generally calcium orthophosphate, can induce bone formation.

With respect to solubility, hydroxyapatite is considered to be sparingly soluble in biological media, while other calcium orthophosphates are even more sparingly, as can be seen from the accompanying table which shows the solubility of various phosphates.

[0011] Apatite has many biological uses. Apatite is used as a filler (in the form of powder or granules), as a dressing (in the form of powder sprayed by plasma spraying), and also as a wedge, screw, intragastric frame, etc. during osteotomy. It can be used in the form of a solid molded body that becomes a highly resistant filling or fixed body. In the latter application, it is necessary to produce apatite in the form of a solid molded body.

(Prior Art) Until now, solid apatite compacts have been subjected to high temperatures (1000
(Temperatures in excess of 0 ° C.).

The literature Bioceramics, Vol. 10, 1997 pp. 75-78 discloses densification of polycrystalline hydroxyapatite, which is compressed at a high temperature of 1165 ° C. under a pressure of 10 MPa.

[0014] Accordingly, in the method currently used for the production of biomaterials consisting of hydroxyapatite, the apatite powder is prepared beforehand, granulated in the form of granules, spontaneously sintered, sintered under pressure and after slip use. It is necessary to perform high temperature sintering by various methods such as sintering.

[0015] In these techniques, a solid molded body having excellent mechanical properties can be obtained, but high-temperature heat treatment is required, so that:-the energy cost of producing apatite is high;-a part of hydroxyapatite is converted to oxyapatite. Transformation,-It is difficult to incorporate volatile or decomposable components into the apatite molded product at the heat treatment temperature.

(Summary of the Invention) More specifically, an object of the present invention is to provide a method for producing apatite ceramics, which has an advantage that a molded body having excellent mechanical properties and requiring no high-temperature heat treatment can be obtained. That is.

The method for producing apatite ceramics according to the present invention includes the steps of (a) Ca (H ₂ PO ₄ ) ₂ , Ca (H ₂ PO ₄ ) ₂ .H ₂ O, Ca (HPO ₄ ), Ca (HPO ₄ )
(HPO ₄ ) · 2H ₂ O, α or β species of Ca ₃ (PO ₄ ) ₂ and Ca ₄ (PO ₄ ) ₂ O
A powder of at least two calcium phosphates selected from the group consisting of a mixture of the powders corresponding to a stoichiometric hydroxyapatite of the formula: Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ (II) or a formula: Ca _{10 -x} V _x (PO ₄ ) _{6 -y} (HPO ₄ ) _y (OH) _{2 + y-2x} (III) wherein V represents a void, x and y are x <1, y <1 and y ≦ x and the atomic ratio Ca / P is less than 1.667], and preparing a homogeneous mixture containing the non-stoichiometric hydroxyapatite in an amount corresponding to (b) the step (a). Compressing the obtained powder mixture at room temperature under a pressure of 100-500 MPa to produce a compression-molded product; and (c) compressing the compacted product at a temperature of 100-500 ° C. in a closed chamber containing an aqueous medium at a temperature of at least 8 ° C. Time thermal hydration treatment.

In the method described above, stoichiometric and non-stoichiometric hydroxyapatite is obtained at low temperatures. Since the temperature used in the final stage does not exceed 500 ° C., it is also advantageous in terms of energy cost, and it is possible to incorporate volatile or unstable components into hydroxyapatite at temperatures exceeding 500 ° C. This is advantageous. The obtained solid compact has excellent mechanical properties and is easy to machine.

The process of the present invention may also comprise a stoichiometric apatite ceramic of the formula: Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ (II) or a formula: Ca _10-x V _x (PO ₄ ) _6-y (HPO ₄ ) _y (OH) _{2 + y−2x} (III) wherein V represents a void, x and y are x <1, y <1 and y ≦ x;
a, PO ₄ and / or OH may be partially replaced by another metal and / or another anion, respectively).

According to this embodiment of the invention, in step (a) at least one selected from salts, oxides and hydroxides of alkali metals, alkaline earth metals, silver or other metals.
A powder mixture consisting of a compound of the type and silicon oxide is prepared, said mixture comprising a stoichiometric apatite of the formula: Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ (II) or a formula: Ca _10-x V _x ( PO ₄ ) _6-y (HPO ₄ ) _y (OH) _{2 + y-2x} (III) wherein V represents a void, x and y are x <1, y <1 and y ≦ x , C
a, PO ₄ and / or OH may be partially substituted by another metal and / or another anion, respectively).

The salts used to prepare this mixture are selected from phosphates, silicates, citrates, nitrates, carbonates and halides.

In this embodiment of the method of the invention, cations and anions which are advantageous for the intended use can be introduced into the apatite structure.

When using the method to produce apatite ceramics for biological applications
, Formula: Ca_TwoSr (PO_Four)_Two  Preparing a powder mixture comprising strontium calcium phosphate, or
Instead of using one or more calcium phosphate compounds, a similar phosphate
Use of rontium compounds or calcium-strontium mixed compounds
And it may be effective to introduce strontium into this structure. Formula: Sr (
H_TwoPO_Four)_Two, Sr (H_TwoPO_Four)_Two・ H_TwoO, Sr (HPO_Four), Sr (PHO_Four)_Two ・ 2H_TwoO, Sr_Three(PO_Four)_TwoAnd Sr_Four(PO_Four)_TwoCompounds of O may be used.

The presence of strontium in apatite ceramics for biological applications has the advantage of promoting bone regeneration.

For biological applications, calcium carbonate may also be added to the powder mixture to obtain calcified apatite similar to bone.

In order to obtain silicified apatite ceramics, ie hydroxyapatite in which the PO ₄ anion has been replaced by the SiO ₄ anion, it has been selected from silicon oxide SiO ₂ , calcium metasilicate CaSiO ₃ and metasilicates of other metals. Silicon compounds may be added to the powder mixture. These silicified apatites can immobilize proteins.

Thus, various materials adapted to the intended use are obtained by the method according to the invention.

The process according to the invention is based on a thermohydration reaction between the various components of the pre-compacted powder mixture.

In step (a) of the method according to the invention, the formula: Ca_Ten(PO_Four)₆(OH)_Two  [Anions and / or cations in the formula are different cations and / or different
Which can be partially substituted by an anion of
To prepare a powder mixture.

A mixture can be prepared by grinding these components to a particle size of less than 100 μm.

[0031] The components of the mixture are selected according to the desired composition.

[0032] That is, when producing calcium phosphate hydroxyapatite apatite ceramics, monocalcium phosphate _{Ca (H 2 PO 4) 2} , hydrated phosphate monobasic calcium _{Ca (H 2 PO 4) 2} · H 2 O Tricalcium phosphate Ca ₃ (PO ₄ ) ₂ , anhydrous bicalcium phosphate Ca (HPO ₄ ), or dihydrated bicalcium phosphate Ca (HPO ₄ ) · 2H ₂ O, α or β species A mixture of various calcium phosphate compounds, such as tetracalcium acid Ca ₄ P ₂ O ₉ , is used in a proportion such that the final composition is hydroxyapatite of the formula Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ (II) .

Use of a mixture containing at least two phosphate compounds comprising one basic compound (tetracalcium phosphate) and one or more acidic compounds (dicalcium phosphate or monocalcium) Is advantageous.

Two or more components may be used in each mixture to help control the composition of the final apatite ceramic.

[0035] Further additives may be added to the powder mixture such that the resulting hydroxyapatite acquires properties that are effective for the intended use.

In the case of apatite ceramics for biological use, pre-fired hydroxyapatite granules, biologically acceptable reinforcing particles, radioactive tracers, and pharmaceutical compounds, bactericides, antibiotics, antibacterials, antimitotics And at least one additive selected from orthopedic and dental bioactive additives, such as growth factors, to the powder mixture provided that these additives are resistant to temperatures above 100 ° C. Would be effective.

In the case of non-living applications, other additives, such as trace amounts of neodymium with luminescent properties,
Minor amounts of additives such as europium II or III may be used.

[0038] Hydroxyapatite granules and reinforcing particles can improve the mechanical properties of the material. Examples of reinforcing particles include alumina and nylon particles.

The addition of a radioactive tracer may also be effective to monitor implant insertion by scintigraphy. The radiotracer may be, for example, a Tc tracer in the form of technetium-99m phosphate.

Antibiotics and bactericides resistant to temperatures above 100 ° C., for example pharmaceutical compounds such as silver, can also be added to the biomaterial.

In another application, nylon or Kevlar may be used to improve mechanical resistance.
Additives such as

After preparation of the powder mixture, optionally containing such additives, the mixture is treated in a compaction step (b).

The compression is carried out at room temperature, for example 15-30 ° C., by applying a pressure of 100-500 MPa, preferably 200 MPa, to the mixture introduced into the mold, for example by means of a hydraulic press.

In the subsequent step (c), the compression-molded body is subjected to a thermal hydration treatment in a closed chamber in the presence of an aqueous medium at a temperature of 100 to 500 ° C. under a pressure corresponding to a steam pressure at a selected temperature.

The water vapor pressure in the closed chamber used for this treatment is preferably 0.5 to 17 MPa.

In this treatment, a ceramic form is obtained by a thermohydration reaction between the compressed components of the mixture. Since apatite needle-like crystals for adjusting (conditioning) aggregation of this material develop inside the solid material, a molded article having extremely excellent hardness can be obtained.

There are two methods for the thermal hydration treatment.

According to a first embodiment of the treatment, the compact is completely immersed in the aqueous medium such that the compact comes into contact with the water in the liquid state.

According to a second embodiment of the hot hydration treatment, which is preferably used for compacts containing compounds soluble in aqueous media, the compacts only contain water vapor generated in a closed chamber under the effect of the treatment temperature. The compression molded body is placed above the aqueous medium so as to contact with.

The temperature of the thermal hydration treatment is in the range of 100-500 ° C., and the duration of this thermal hydration treatment depends in particular on the use temperature, the lower the temperature the longer the duration. The duration is generally at least 8 hours and can be up to 60 hours.

The temperature of the thermal hydration treatment is preferably 150-250 ° C., and the duration is about 48 hours.

[0052] The aqueous medium used is usually deionized water, but aqueous solutions containing suitable additives may also be used.

In order to reduce the solubility of hydroxyapatite, an aqueous solution of sodium fluoride for introducing fluorine ions into the structure of hydroxyapatite may be used as the aqueous medium. The addition of sodium fluoride to the aqueous medium is particularly suitable for the production of apatite ceramics for biological applications.

According to a variant embodiment of the method according to the invention, the method comprises the additional step (d) of sintering the compact obtained from the hot hydration process. The sintering is performed at a temperature of at least 1,000C, preferably 1,000-1,300C.

In this way, a very highly compacted material with excellent mechanical properties is obtained.

As described above, the method of the present invention is very advantageous because it can produce apatite ceramics of various compositions depending on the compound used in the starting mixture. Further, by using the mixture components in an amount such that the total atomic ratio of Ca / P is less than 1.667, non-stoichiometric apatite having a Ca / P atomic ratio of less than 1.667 can be obtained by the method of the present invention. Can be manufactured.

The production of non-stoichiometric apatite results in a biocompatible compound that is more soluble than stoichiometric hydroxyapatite and therefore very advantageous. This property is particularly useful for producing shaped bodies that can be resorbed and then replaced by newly formed bone tissue by the organism.

Non-stoichiometric apatite is also obtained by adjusting the duration of the hot hydration treatment step so as to obtain an apatite mixed with one of the starting calcium phosphates, such as tricalcium phosphate. When reacted for such a duration that the reaction is not completed, tricalcium phosphate that does not transform into hydroxyapatite by the thermohydration reaction will remain to some extent in the molded body.

Other features and advantages of the present invention will become more clearly apparent from the following description of non-limiting embodiments based on the accompanying drawings.

EXAMPLES Example 1 Production of Calcium Phosphate-Based Hydroxyapatite In this example, three types of calcium phosphate were first used: hydrated monocalcium phosphate Ca (H ₂ PO ₄ ) ₂ .H ₂ O - tricalcium phosphate Ca ₃ (PO _{4) 2} and - tetracalcium phosphate Ca ₄ (PO ₄₎ to prepare a powder mixture consisting of ₂ O.

The proportion of each component is calculated from the following reaction: a Ca (H ₂ PO ₄ ) ₂ .H ₂ O + b Ca ₃ (PO ₄ ) ₂ + c Ca ₄ (PO ₄ ) ₂ O
→ Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ (in the presence of water) [where the relationship between the coefficients a, b and c is represented by the following formula: b = 2-3a, c = 1 + 2a, where 0 ≦ a ≦ 0.67; 0 ≦ b ≦ 2 and 1 ≦ c ≦ 2.33].

In this example, the following values are used: a = 0.225 b = 1.325 and c = 1.45.

After forming a homogenous mixture by grinding to a particle size of less than 100 μm, the powder mixture is introduced into a mold, which is then pressed into a mold by a hydraulic press at 200 MPa.
The compression process is performed by applying the pressure of a.

The compact is removed from the mold, introduced into an autoclave containing deionized water, and completely immersed in the deionized water. After closing the autoclave, it is introduced into a heating chamber and heated at 200 ° C. for 48 hours.

As a result, a sufficiently crystallized calcium-based hydroxyapatite molded product is obtained.

FIG. 1 shows an X-ray diffraction diagram of the material thus obtained. The figure shows that a small amount of tricalcium phosphate remains.

Prolonging the time that the mixture is maintained in the autoclave converts the residual tricalcium phosphate to hydroxyapatite in the aqueous medium.

Observation with a scanning electron microscope reveals the presence of large needle crystals of calcium-based hydroxyapatite. That is, a sufficient crystallinity of the product is confirmed.

The mechanical resistance of this material to compression is close to 100 MPa.

This material can be easily machined and is particularly suitable as an artificial aggregate.

Example 2 Preparation of Calcium Phosphate-Based Hydroxyapatite In this example, a phosphate mixture similar to that of Example 1 was prepared.
Compress under the same conditions.

The compact is removed from the mold and introduced into an autoclave containing deionized water, but placed above the water level so that the reaction takes place in a steam medium.

The autoclave is closed, introduced into a heating chamber and heated at 200 ° C. for 48 hours.

After the end of the treatment, a material having properties similar to those of the material of Example 1 is obtained.

Example 3 Preparation of Strontium-Containing Apatite Ceramics This example demonstrates hydrated monocalcium phosphate, tricalcium phosphate and
Phosphate of calcium and calcium_TwoSr (HPO_Four)_TwoThe starting material is a powder mixture of The proportion of each component is calculated from the following reaction: a Ca (HPO_Four)_Two・ H_TwoO + b Ca_FourSr (PO_Four)_Two+ C Ca_Four(PO_Four) _Two O → Ca₉Sr (PO_Four)₆(OH)_Two  Where: a = 0.34 b = 1 c = 1.66.

The components are mixed by milling, and the powder mixture is then introduced into a mold,
A compression process is performed by applying a pressure of 190 MPa with a hydraulic press. The obtained compression molded body is introduced into an autoclave and covered with deionized water. Then close the autoclave and bring the temperature to 200 ° C. This corresponds to a steam pressure of 1.6 MPa. 72
Maintain time.

As a result, a calcium-strontium-based hydroxyapatite which is effective as a biological material particularly suitable for promoting bone regeneration can be obtained.

The obtained material has a compression resistance of more than 100 MPa.

The process of the present invention can produce apatite ceramics with excellent mechanical properties, particularly suitable for biological applications, and can incorporate various additives that impart improved mechanical or other properties to these ceramics. So it is a very useful method.

[0080]

[Table 1]

(Reference) Bioceramics, Vol. 10, 1997 pp. 75-78

[Brief description of the drawings]

FIG. 1 is an X-ray diffraction diagram showing a structure of an apatite ceramic obtained in Example 1.

──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Lac, Jean-Louis, France, F-31000-Touruz, Rille-de-la-Colombet, 36 (72) Inventor Freixille, Michel France, F-31130 Huongs Grib, Liu Dou Cerdanuille, 3F term (reference) 4C081 AB03 BA12 CE01 CE02 CF031 CF24 CF25 CG07 4C089 AA01 BA03 BA08 BA09 BA10 BA14 BA16 BB04 BC05 CA02 CA07 4G030 AA08 AA37 AA41 BA35 CA01 GA04 GA19 GA27

Claims (18)

[Claims] 1. A _{(a) Ca (H 2 PO} 4) 2, Ca (H 2 PO 4) 2 · H 2 O, C a (HPO 4), Ca (HPO 4) · 2H 2 O, α or β At least two calcium phosphate powders selected from the species Ca ₃ (PO ₄ ) ₂ and Ca ₄ (PO ₄ ) ₂ O, the mixture of which has the formula: Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ Or a formula corresponding to the stoichiometric hydroxyapatite of formula (II): Ca _10-x V _x (PO ₄ ) _6-y (HPO ₄ ) _y (OH) _{2 + y-2x} (III) V represents a void, x and y are x <1, y <1 and y ≦ x, and the atomic ratio Ca / P is less than 1.667]. Preparing a homogeneous mixture comprising: (b) subjecting the powder mixture obtained in step (a) to room temperature under a pressure of 100-500 MPa. And (c) subjecting the compression molded body to a thermohydration treatment at a temperature of 100-500 ° C. for at least 8 hours in a closed chamber containing an aqueous medium. Production method. 2. In step (a), an alkali metal, an alkaline earth metal, silver or
At least one compound selected from salts, oxides and hydroxides of other metals
Preparing a powder mixture comprising silicon oxide, said mixture having the formula: Ca_Ten(PO_Four)₆(OH)_Two  Of the stoichiometric hydroxyapatite or of the formula:_10-xV_x(PO_Four)_6-y(HPO_Four)_y(OH)_{2 + y-2x} (III) wherein V represents a void, x and y are x <1, y <1 and y ≦ x, and C
a, PO_FourAnd / or OH may be partially replaced by another metal and / or another anion, respectively).
The method of claim 1, wherein: 3. The method according to claim 2, wherein the salt is selected from phosphate, silicate, citrate, nitrate, carbonate and halide. 4. The powder mixture of the formula: Ca_TwoSr (PO_Four)_Two  Or strontium calcium phosphate of the formula or Sr (H_TwoPO_Four)_Two, Sr (H_TwoPO_Four)_Two・ H_TwoO, Sr (HPO_Four), Sr (PHO_Four)_Two・ 2H_TwoO, S
r_Three(PO_Four)_TwoAnd Sr_Four(PO_Four)_TwoCharacterized by containing a strontium compound of O
The method according to claim 3 for producing apatite ceramics for biological use.
Law. 5. The method according to claim 3, wherein the powder mixture comprises calcium carbonate, for producing apatite ceramics for biological use. 6. A process for producing apatite ceramics for biological use, characterized in that the powder mixture comprises a silicon compound selected from silicon oxide SiO ₂ , calcium metasilicate CaSiO ₃ and metasilicate of another metal. A method according to any one of claims 3 to 5. 7. As an additional step, (d) the compression-molded body obtained by the thermal hydration treatment in step (c) is at least 1,000.
The method according to any of the preceding claims, comprising sintering at a temperature of ° C. 8. The process according to claim 1, wherein in step (a) a powder mixture is prepared by grinding the components. 9. The method according to claim 1, wherein in step (c), the compact is completely immersed in an aqueous medium. 10. The method according to claim 1, wherein in step (c), the compact is placed above the aqueous medium. 11. The steam pressure in the closed chamber used in step (c) is 0.5-1.
The method according to claim 9, wherein the pressure is 7 MPa. 12. The method as claimed in claim 1, wherein the duration of the thermal hydration treatment is between 8 and 60 hours. 13. The method according to claim 1, wherein the aqueous medium is deionized water. 14. Pre-baked hydroxyapatite granules, biologically acceptable reinforcing particles, radiotracers, and pharmaceutical compounds, fungicides, antibiotics,
Claims for producing apatite ceramics for biological use, characterized in that at least one additive selected from a bioactive substance selected from an antimicrobial agent, an antimitotic agent and a growth factor is added to the powder mixture. Item 14. The method according to any one of Items 1 to 13. 15. The method according to claim 14, wherein the radioactive tracer is technetium-99m phosphate. 16. The method according to claim 14, wherein the germicide is silver. 17. The method according to claim 1, wherein the aqueous medium used in step (c) comprises sodium fluoride, for producing apatite ceramics for biological use. . 18. The method according to claim 1, wherein the powder mixture further comprises a luminescent additive and / or a mechanical resistance improving additive.